Juvenile hypothyroidism among two populations exposed to radioiodine.
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We found an epidemic of juvenile hypothyroidism among a population of self-defined "downwinders" living near the Hanford nuclear facility located in southeast Washington State. The episode followed massive releases of 131I. Self-reported data on 60 cases of juvenile hypothyroidism (<20 years of age) among a group of 801 Hanford downwinders are presented, as well as data concerning the thyroid status of approximately 160,000 children exposed to radioiodine before 10 years of age as a result of the 26 April 1986 Chernobyl explosion in the former Soviet Union. These children were residents of five regions near Chernobyl. They were examined by standardized screening protocols over a period of 5 years from 1991 to 1996. They are a well-defined group of 10 samples. Fifty-six cases of hypothyroidism were found among boys and 92 among girls. Body burdens of 137Cs have been correlated with hypothyroidism prevalence rates. On the other hand, the group of juvenile (<20 years of age) Hanford downwinders is not a representative sample. Most of the 77 cases of juvenile hypothyroidism in the Hanford group were diagnosed from 1945 to 1970. However, the ratio of reported cases to the county population under 20 years of age is roughly correlated with officially estimated mean levels of cumulative thyroid 131I uptake in these counties, providing evidence that juvenile hypothyroidism was associated with radioiodine exposures. Because even subtle hypothyroidism may be of clinical significance in childhood and can be treated, it may be useful to screen for the condition in populations exposed to radioiodine fallout. Although radiation exposure is associated with hypothyroidism, its excess among fallout-exposed children has not been previously quantified. (+info)
Fibroblast radiosensitivity measured using the comet DNA-damage assay correlates with clonogenic survival parameters.
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A study was made of the neutral comet assay as a potential method for measuring normal cell radiosensitivity. Eleven fibroblast strains were studied comprising nine derived from vaginal biopsies from pretreatment cervical cancer patients and two strains from radiosensitive individuals. DNA double strand break (dsbs) dose-response curves for both initial and residual (20-h repair time) damage were obtained over the dose range 0-240 Gy, with slopes varying 3.2 and 8-fold respectively. Clonogenic cell survival parameters were available for all the cell strains following both high- and low-dose rate irradiation. There were no correlations between the dose-response slope of the initial level of DNA dsbs and parameters that mainly describe the initial portion of clonogenic radiation survival curves (SF2, alpha, D). A significant correlation (r = -0.63, P = 0.04) was found between the extent of residual DNA dsbs and clonogenicity for all 11 fibroblast strains. The parameter showing the highest correlation with fibroblast cell killing (D) for the nine normal fibroblasts alone was the ratio of initial/residual DNA dsb dose-response slope (r = 0.80, P = < 0.01). A significant correlation (r = -0.67, P = 0.03) with clonogenic radiosensitivity was also found for all 11 cell strains when using the ratio of initial/residual DNA dsb damage at a single dose of 180 Gy. This study shows that fibroblast radiosensitivity measured using the neutral comet assay correlates with clonogenic radiation survival parameters, and therefore may have potential value in predictive testing of normal tissue radiosensitivity. (+info)
Activation of the CD95 (APO-1/Fas) pathway in drug- and gamma-irradiation-induced apoptosis of brain tumor cells.
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Chemotherapeutic agents and gamma-irradiation used in the treatment of brain tumors, the most common solid tumors of childhood, have been shown to act primarily by inducing apoptosis. Here, we report that activation of the CD95 pathway was involved in drug- and gamma-irradiation-induced apoptosis of medulloblastoma and glioblastoma cells. Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine/paracrine loop. Blocking CD95-L/receptor interaction using F(ab')2 anti-CD95 antibody fragments strongly reduced apoptosis. Apoptosis depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3 like proteases) as it was almost completely abrograted by the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP. Moreover, CD95 was upregulated in wild-type p53 cells thereby increasing responsiveness towards CD95 triggering. Since activation of the CD95 system upon treatment was also found in primary medulloblastoma cells ex vivo, these findings may have implications to define chemosensitivity and to develop novel therapeutic strategies in the management of malignant brain tumors. (+info)
Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor.
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Ewing's sarcoma (EWS) cells accumulate elevated steady-state levels of poly (ADP-ribose) polymerase (PARP) mRNA and protein. To understand the molecular mechanisms underlying PARP upregulation, we cloned and analysed the 5'-flanking region of the PARP gene from EWS cells. Nucleotide sequence analysis demonstrated no variations in the PARP promoter region in EWS cells. The PARP promoter encompasses multiple binding motifs for the ETS transcription factor. We have also observed that there is a coordinated up-regulation of the expression of both PARP and ETS1, relative to cells of other human tumor types expressing lower levels of PARP. Transient co-expression of ETS1 in EWS cells resulted in a strong enhancement of PARP-promoter activity. The participation of ETS in the regulation of PARP gene expression was further demonstrated in EWS cells stably transfected with Ets1 antisense cDNA constructs. Antisense-mediated down-regulation of endogenous ETS1 resulted in the inhibition of PARP expression in EWS cells, and sensitized these cells to ionizing radiation. These data provide support for ETS regulation of PARP expression levels, and implicate ETS transcription factors in the radiation response of EWS cells. (+info)
Clinical evaluation of processing techniques for attenuation correction with 137Cs in whole-body PET imaging.
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Transmission scanning can be successfully performed with a 137Cs single-photon emitting point source for three-dimensional PET imaging. However, the attenuation coefficients provided by this method are underestimated because of the energy difference between 662- and 511-keV photons, as well as scatter and emission contamination when the transmission data are acquired after injection. The purpose of this study was to evaluate, from a clinical perspective, the relative benefits of various processing schemes to resolve these issues. METHODS: Thirty-eight whole-body PET studies acquired with postinjection singles transmission scans were analyzed. The transmission images were processed and applied to the emission data for attenuation correction. Three processing techniques were compared: simple segmentation (SEG) of the transmission scan, emission contamination subtraction with scaling (ECS) of the resulting data to 511-keV attenuation coefficient values and a hybrid technique performing partial segmentation of some tissue densities on the ECS scan (THR). The corrected emission scans were blindly assessed for image noise, the presence of edge artifacts at the lung-soft-tissue interface and for overall diagnostic confidence using a semiquantitative scoring system. The count densities and the SDs in uniform structures were compared among the various techniques. The observations for each method were compared using a paired t test. RESULTS: The SEG technique produced images that were visually less noisy than the ECS method (P < 0.0001) and the THR technique, but at the expense of increased edge artifacts at the boundaries between the lungs and surrounding tissues. The THR technique failed to eliminate these artifacts compared with the ECS technique (P < 0.0001) but preserved the activity gradients in the hilar areas. The count densities (and thus, the standardized uptake values) were similar among the three techniques, but the SEG method tended to underestimate the activity in the lung fields and in chest tumors (slope = 0.79 and 0.94, respectively). CONCLUSION: For many clinical applications, SEG data remain an efficient method for processing 137Cs transmission scans. The ECS method produced noisier images than the other two techniques but did not introduce artifacts at the lung boundaries. The THR technique, more versatile in complex anatomic areas, allowed good preservation of density gradients in the lungs. (+info)
Environmental radioactivity, population exposure and related health risks in the east Baltic region.
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The paper considers radioactive contamination of the east Baltic region, population exposures, and the risk of damage to human health. Principal sources include global fallout, the Chernobyl accident, and marine transport of radionuclides. A mean annual exposure of 2-3 mSv comes from environmental radioactivity. Main contributors are primarily radon and its decay products. The Chernobyl accident brought an additional dose of about 0.5 mSv in southern Finland and 1.4 mSv in the most contaminated districts of the Leningrad region, Russia. Both external and internal exposure via contaminated food contributed. Currently, significant long-term radiological consequences of the Chernobyl accident include persistent radioactive contamination of natural terrestrial (forest) and freshwater (oligotrophic lakes) ecosystems and food products. Radiation health risks are lung cancer among the general population from indoor exposure to radon, acute radiation syndrome from occupational exposure, thyroid cancer among children in heavily contaminated non-Baltic areas, and mutations among offspring of exposed parents. (+info)
Remote afterloading endocurie therapy for carcinoma of the cervix.
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Since October 1975, 41 cancer patients were treated with a remote afterloading device using fractionated high dose-rate intracavitary radiation. Nineteen of these 41 patients were treated for carcinoma of the cervix. Remote afterloading high dose-rate fractionated intracavitary radiation was given in combination with external irradiation. The dose fractionation and rad equivalent therapeutic (RET) values and various points of interest are discussed. (+info)
Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency.
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Injury to the central nervous system (CNS) by ionizing radiation may be a consequence of damage to the vascular endothelium. Recent studies showed that radiation-induced apoptosis of endothelial cells in vitro and in the lung in vivo is mediated by the lipid second messenger ceramide via activation of acid sphingomyelinase (ASM). This apoptotic response to radiation can be inhibited by basic fibroblast growth factor or by genetic mutation of ASM. In the CNS, single-dose radiation has been shown to result in a 15% loss of endothelial cells within 24 h, but whether or not this loss is associated with apoptosis remains unknown. In the present studies, dose- and time-dependent induction of apoptosis was observed in the C57BL/6 mouse CNS. Apoptosis was quantified by terminal deoxynucleotidyl transferase-mediated nick end labeling, and specific endothelial apoptosis was determined by histochemical double labeling with terminal deoxynucleotidyl transferase-mediated nick end labeling and Lycopersicon esculentum lectin. Beginning at 4 h after single-dose radiation, apoptosis was ongoing for 24 h and peaked at 12 h at an incidence of 0.7-1.4% of the total cells in spinal cord sections. Up to 20% of the apoptotic cells were endothelial. This effect was also seen in multiple regions of the brain (medulla, pons, and hippocampus). A significant reduction of radiation-induced apoptosis was observed after i.v. basic fibroblast growth factor treatment (0.45-4.5 microg/mouse). Identical results were noted in C3H/HeJ mice. Furthermore, irradiated ASM knockout mice displayed as much as a 70% reduction in endothelial apoptosis. This study demonstrates that ionizing radiation induces early endothelial cell apoptosis throughout the CNS. These data are consistent with recent evidence linking radiation-induced stress with ceramide and suggest approaches to modify the apoptotic response in control of radiation toxicity in the CNS. (+info)